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Zusammenfassung Ziel der Studie Bei der Behandlung von Patienten mit rheumatoider Arthritis sind Haus- und Fachärzte, Pflegedienste, Ergo- und Physiotherapeuten sowie verschiedene andere Berufsgruppen beteiligt. Ziel dieser Studie ist eine Beschreibung dieser interprofessionellen Kooperationen in der alltäglichen Versorgungspraxis aus hausärztlicher Sicht. Methodik Mittels einer Querschnittserhebung wurden von Februar bis September 2017 die Kooperationen von Hausärzten (n=121 in 68 Praxen) in Hessen und Rheinland-Pfalz mit verschiedenen anderen Versorgern erfasst. Diese Querschnittserhebung war in die prospektive Kohortenstudie PANORA (Prävalenz von Anti-CCP-Antikörpern bei Patienten mit neuen Beschwerden am Bewegungsapparat) integriert. Der verwendete Fragebogen für Hausärzte enthielt geschlossene Fragen zu Soziodemografie, Häufigkeit, Gewichtung und Bewertung der bestehenden Kooperationen. Die erhobenen Daten wurden deskriptiv ausgewertet. Ergebnisse Bei Betrachtung der von Hausärzten übernommenen Aufgaben, gaben mehr als 70% der Ärzte an bei der Betreuung ihrer Patienten mit rheumatoider Arthritis „oft“ die Koordination der Medikamente, Gespräche über die Diagnose und Laborkontrollen durchzuführen. Die häufigste Kooperation mit der größten Wichtigkeit und einer geringen Zufriedenheit ergab sich mit den Rheumatologen. Als zweithäufigste Kooperation und hoher Wichtigkeit wurde die Kooperation mit den Physiotherapeuten bewertet. Die höchste Zufriedenheit wurde mit der Zusammenarbeit mit Pflegediensten beschrieben. Schlussfolgerung Die vorliegende Studie zeigt, dass Hausärzte bei der Versorgung von Patienten mit rheumatoider Arthritis in jedem Stadium der Versorgung verschiedene Versorgungsaufgaben übernehmen und dabei unterschiedlich häufig mit anderen Versorgern zusammenarbeiten. Insbesondere die Zusammenarbeit mit den Rheumatologen und den Physiotherapeuten ist den Hausärzten wichtig. Jedoch wurde die Kooperation mit Rheumatologen als unzureichend und verbesserungswürdig beurteilt.

As students move through the grades, content area learning becomes increasingly significant for reading, writing, and speaking tasks. One research-evidenced approach to actively engaging adolescent...

General practitioners, specialists, occupational and physical therapists, nursing services and other professional groups are all involved in the treatment of patients with rheumatoid arthritis. This study aims to describe interprofessional cooperation in daily ambulatory care from the perspective of a general practitioner.The cross-sectional study investigated cooperation between general practitioners (n=121 in 68 medical practices) and several other health care providers in Hesse and Rhineland Palatinate, Germany, from February to September 2017. It was part of the prospective cohort study PANORA (Prevalence of anti-cyclic citrullinated peptide (anti-CCP) positivity in patients with new onset of non-specific musculoskeletal symptoms). The questionnaire that was used contained closed-ended questions on socio-demographics and frequency of contact, and asked physicians to assess and weigh existing collaboration. Descriptive statistics were used for data analysis.When caring for patients with rheumatoid arthritis, 70%, of the physicians often took responsibility for synchronizing medications, and discussing diagnoses and test results. The most frequent cooperation was with rheumatologists and was considered as highly important but the least satisfactory. The second most frequent cooperation was with physical therapists and this was also rated as very important. Physicians had highest level of satisfaction with their collaboration with the nursing services.This study shows that general practitioners perform several medical tasks when treating patients with rheumatoid arthritis. During the process, they work together with several health care providers to various degrees. Cooperation with rheumatologists and physical therapists is particularly important to general practitioners; cooperation with rheumatologists is considered inadequate and in need of improvement.Bei der Behandlung von Patienten mit rheumatoider Arthritis sind Haus- und Fachärzte, Pflegedienste, Ergo- und Physiotherapeuten sowie verschiedene andere Berufsgruppen beteiligt. Ziel dieser Studie ist eine Beschreibung dieser interprofessionellen Kooperationen in der alltäglichen Versorgungspraxis aus hausärztlicher Sicht.Mittels einer Querschnittserhebung wurden von Februar bis September 2017 die Kooperationen von Hausärzten (n=121 in 68 Praxen) in Hessen und Rheinland-Pfalz mit verschiedenen anderen Versorgern erfasst. Diese Querschnittserhebung war in die prospektive Kohortenstudie PANORA (Prävalenz von Anti-CCP-Antikörpern bei Patienten mit neuen Beschwerden am Bewegungsapparat) integriert. Der verwendete Fragebogen für Hausärzte enthielt geschlossene Fragen zu Soziodemografie, Häufigkeit, Gewichtung und Bewertung der bestehenden Kooperationen. Die erhobenen Daten wurden deskriptiv ausgewertet.Bei Betrachtung der von Hausärzten übernommenen Aufgaben, gaben mehr als 70% der Ärzte an bei der Betreuung ihrer Patienten mit rheumatoider Arthritis „oft“ die Koordination der Medikamente, Gespräche über die Diagnose und Laborkontrollen durchzuführen. Die häufigste Kooperation mit der größten Wichtigkeit und einer geringen Zufriedenheit ergab sich mit den Rheumatologen. Als zweithäufigste Kooperation und hoher Wichtigkeit wurde die Kooperation mit den Physiotherapeuten bewertet. Die höchste Zufriedenheit wurde mit der Zusammenarbeit mit Pflegediensten beschrieben.Die vorliegende Studie zeigt, dass Hausärzte bei der Versorgung von Patienten mit rheumatoider Arthritis in jedem Stadium der Versorgung verschiedene Versorgungsaufgaben übernehmen und dabei unterschiedlich häufig mit anderen Versorgern zusammenarbeiten. Insbesondere die Zusammenarbeit mit den Rheumatologen und den Physiotherapeuten ist den Hausärzten wichtig. Jedoch wurde die Kooperation mit Rheumatologen als unzureichend und verbesserungswürdig beurteilt.

Residents in long-term care facilities (LTCF) are a vulnerable population group. Coronavirus disease (COVID-19)-related deaths in LTCF residents represent 30–60% of all COVID-19 deaths in many European countries. This situation demands that countries implement local and national testing, infection prevention and control, and monitoring programmes for COVID-19 in LTCF in order to identify clusters early, decrease the spread within and between facilities and reduce the size and severity of outbreaks.

Basophils are effector cells that respond to protease allergens and parasites, thus contributing to allergic inflammation and Th2 differentiation. However, the molecular interactions through which pathogens promote activation as well as recruitment of these cells to sites of inflammation remain poorly understood. We found that administration of extracts from Nippostrongylus brasiliensis induced both basophil recruitment into blood and liver in vivo and IL-4 and histamine production by purified bone marrow-derived basophils in vitro. Starting from this finding, we set out to identify putative pathogen-derived molecules for their capacity to activate murine basophils, using a basophil population differentiated and expanded from bone marrow cells cultured with IL-3 and sorted as a CD49b+ c-kit– subset. Among a number of Toll-like receptor (TLR) agonists tested, we found that the lipopeptide Pam2CSK4 and lipopolysaccharide (LPS) activate basophils in terms of IL-4, IL-6 and histamine production through TLR2 and TLR4, respectively. By contrast, TLR3 or TLR7 agonists had no such effect. We further identified nitric oxide (NO) as key mediator for LPS stimulation and established that in vivo administration of LPS led to basophil recruitment into the liver. Our results reveal the important contribution of MyD88 and NO signaling to antigen recognition through TLR2 and TLR4 pathways leading to activation, degranulation and release of immunoregulatory mediators.

Introduction Women and men are different, and the jobs they do, their working conditions and circumstances and how society treats them are different, affecting the occupational risks they face: a gender-sensitive prevention approach is required. However, gender mainstreaming and taking a gender-sensitive approach are not always well understood in OSH. Practice needs to be exchanged and experiences shared in order to debunk some of the myths and barriers. This project researched examples of policies, programmes and practices from across the EU and worldwide to illustrate gender approaches in OSH. Methods The cases cover approaches by national and intermediary organisations and gender-sensitive approaches to OSH in the workplace. Detailed descriptions of a range of cases were made, covering the development process and what was achieved. Brief summaries of additional examples were made. The cases were analysed for success factors, challenges, drivers and transferability. Results The cases were varied, covering: integrating gender mainstreaming into organisations’ planning, administration and daily working practices; developing methods and tools to promote gender mainstreaming; facilitating working conditions suitable for both women and men, including both health and human resources management; the reconciliation of work and family life and thereby promoting better work–life balance; ensuring women are encouraged and supported in working in male-dominated professions; designing and promoting personal protective equipment (PPE) for women; conducting awareness-raising campaigns on health. Discussion Men and women benefit when gender differences are recognised and are addressed in OSH. The report shows that this is happening in many different ways, through policy and strategy, research and at the workplace. Those taking action include scientific associations, OSH organisations, equalities organisations, health organisations, employers and trade unions. The cases range from comprehensive gender-mainstreaming projects to simple steps that organisations can take to ensure that the OSH of both male and female workers is covered.

Cancer is considered to be the leading cause of work-related deaths in the EU, with an estimated 1 20 000 new cases and about 80 000 deaths per year. It is clear that more can be done to reduce the number of cases of occupational cancer, which is why, on 25 May 2016, EU-OSHA together with five partners signed a covenant committing to a voluntary action scheme to raise awareness of the roadmap for carcinogens 2016–2019. The scheme aims to engage many more organisations, companies and all those concerned in the fight against work-related cancer. EU-OSHA will intensify its efforts to raise awareness of the risks from the exposure to carcinogens at work during its Health Workplaces campaign 2018–2019, which is dedicated to the management of risks from dangerous substances at work. A core task of EU-OSHA is to help share solutions – good practices and initiatives from companies, authorities, labour inspections, trade associations and unions at the national and at the European level. To support the roadmap, EU-OSHA therefore engages with national partners in their activities and provide them with a basic set of tools and instruments to raise awareness of this important topic, including information sheets, case studies, and a database of tools and instruments. EU-OSHA is also committed to organising regular international stock-taking events where best practice examples are presented and progress is discussed from the point of view of all the actors involved in improving prevention. This presentation focuses on a range of activities that help fulfil the common goal of reducing the death toll from exposure to carcinogens to underline the role that every actor can play.

Aim of special session Roadmap on carcinogens – EU and national initiatives (3rd May 2018) EU-OSHA and its Dutch partners will update the audience about the roadmap’s activities and those of the 2018/19 Healthy Workplaces Campaign on dangerous substances. This will be complemented by a report from the workplace level, and the audience will be actively engaged in discussions about future priorities and challenges in this important field of OSH action. Laurie Hermans 1 , Wouter Fransman 2 1 TNO, Leiden, The Netherlands 2 TNO, Zeist, The Netherlands

Der Beitrag formuliert die These, dass die Beliebtheit des Resilienzbegriffs trotz seiner definitorischen Unscharfe mit einer veranderten Wahrnehmung von Unsicherheit, Krisen und Risiken zu erklaren ist. Seine Popularitat steht in Verbindung zu dem dominanten Selbstbeschreibungsmodus der Reflexiven Moderne – der Krise –, die sich in einer auf Dauer gestellten Unsicherheitswahrnehmung niederschlagt. Auf diese Verunsicherung scheint Resilienz eine hoffnungsvolle Antwort geben zu konnen, weshalb der Begriff in unterschiedlichen Anwendungskontexten, von der individuellen Stressbewaltigung bis hin zu sicherheitspolitischen Legitimationsstrategien, als der vielversprechende Versuch gepriesen wird, unvorhersehbare, krisenhafte Ereignisse aller Art, zunehmend aber auch gesellschaftliche Steuerungsprobleme auf eine ganz neue Weise handhabbar zu machen. Allerdings kann der Resilienzbegriff dieser Hoffnung nicht entsprechen. Hingegen wird mit dessen Einsatz einerseits uber die Begrundungsbedurftigkeit bestehender gesellschaftlicher Institutionen und Systeme hinweggetauscht. Dabei werden kritische Auseinandersetzungen umgangen. Einhergehend mit dieser Form der Entpolitisierung der gesellschaftlichen Zukunftsgestaltung und -bewaltigung besteht andererseits die Gefahr der Uberlastung jeder/s Einzelnen. Letztendlich steht der Resilienzbegriff dem gesellschaftlichen Wandel im Weg.

The evolution of allergic asthma is tightly controlled by effector and regulatory cells, as well as cytokines such as IL-10 and/or TGF-β, and it is widely acknowledged that environmental exposure to allergens and infectious agents can influence these processes. In this context, the recognition of pathogen-associated motifs, which trigger TLR activation pathways, plays a critical role with important consequences for disease progression and outcome. We addressed the question whether the TLR7 ligand resiquimod (R848), which has been shown to be protective in several experimental allergic asthma protocols, can also suppress typical asthma symptoms once the disease is established. To this end, we used an OVA-induced experimental model of murine allergic asthma in which R848 was injected after a series of challenges with aerosolized OVA. We found that the treatment attenuated allergic symptoms through a mechanism that required Tregs, as assessed by the expansion of this population in the lungs of mice having received R848, and the loss of R848-mediated suppression of allergic responses after in vivo Treg depletion. IL-10 provided only a minor contribution to this suppressive effect that was largely mediated through a TGF-β-dependent pathway, a finding that opens new therapeutic opportunities for the pharmacological targeting of Tregs.

Activation of invariant natural killer T (iNKT) cells by treatment with their α-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-γ production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.

In U.S. public schools, the population of nonnative speakers of English who are at risk for failing language requirements is growing. This article presents multisensory structured language (MSL) teaching strategies to remediate these students' difficulties in reading, writing, and speaking English. These strategies are underscored by recent findings of cross-linguistic studies. The MSL strategies are evidence-based and can be applied to any language. They are supported by a variety of teaching resources to assist instructors in helping at-risk English language learners improve their English language skills.

Histamine (HA) is a biogenic amine with multiple activities in the immune system. In this study we demonstrate that histamine-free histidine decarboxylase-deficient (HDC−/−) mice present a numerical and functional deficit in invariant NK T (iNKT) cells as evidenced by a drastic decrease of IL-4 and IFN-γ production. This deficiency was established both by measuring cytokine levels in the serum and intracellularly among gated iNKT cells. It resulted from the lack of HA, because a single injection of this amine into HDC−/− mice sufficed to restore normal IL-4 and IFN-γ production. HA-induced functional recovery was mediated mainly through the H4 histamine receptor (H4R), as assessed by its abrogation after a single injection of a selective H4R antagonist and the demonstration of a similar iNKT cell deficit in H4R−/− mice. Our findings identify a novel function of HA through its H4R and suggest that it might become instrumental in modulating iNKT cell functions.

Students with learning disabilities struggle to acquire essential mathematical concepts and skills, especially at the secondary level. One effective approach to improving secondary math performance supported by research is the concrete-to-representational-to-abstract (CRA) sequence of instruction. Although CRA is an evidenced-based instructional practice, it is somewhat complicated for teachers to implement in their day-to-day instruction.To better assist implementation of the CRA, an instructional approach with the mnemonic CRA-MATH was developed as a flexible roadmap to help math teachers better address student deficits using the CRA sequence of instruction. The purpose of this article is to describe the seven-step strategy used to guide curricular CRA modifications in secondary mathematics.

To estimate the individual absorbed dose to the parotid and submandibular salivary glands in radioiodine therapy and its dependence from the previous cumulative therapy.Fifty-five patients with differentiated thyroid carcinoma after thyroidectomy received 1-21 GBq (131)I using single activities of 1-6 GBq. The patients were stratified according to the cumulative activities into low-activity (1-2 GBq), middle-activity (3-7 GBq), and high-activity groups (9-21 GBq). The time-activity curves over the respective salivary glands were derived from multiple static calibrated images measured for each patient up to 48 h after ingestion of the radioiodine therapy capsule with a gamma camera. Manually drawn regions of interests were used to determine the background activities and the activities arising from the salivary glands. The gland volumes were determined by ultrasonography using appropriate volume models.The median absorbed dose per administered activity of each single parotid and submandibular gland was about 0.15 Gy.GBq (range, 0.1-0.3 Gy.GBq(-1)) and 0.48 Gy.GBq(-1) (range, 0.2-1.2 Gy.GBq(-1)), respectively. The maximum uptake of both gland types was significantly lower for the high-activity than for the low-activity groups and correlated with the mean cumulative administered activity of the activity groups.The iodine uptake of salivary glands is significantly reduced, whereas the absorbed dose per administered (131)I activity was not significantly decreased during the course of therapy. Comparing the well-known dose-effect relationships in external radiation therapy, the absorbed dose per administered (131)I activity is too low to induce comparable radiation damage, suggesting an inhomogeneous distribution of (131)I in human salivary glands.

Because of their difficult identification and isolation, the functions of basophils have remained enigmatic for some time. It is well-established that they play a crucial role during helminth infections and allergic diseases, and are most proficient in producing IL-4 together with histamine, which both facilitate Th2 differentiation (1–4). Even before complete maturation—when the typical granules for histamine storage are few—they constitute an excellent source of pro-Th2 cytokines and histamine, which they synthesize in response to growth factors like IL-3 or other stimuli (5). This newly generated histamine is not stored inside the cells but is released immediately to accumulate in the supernatant (5). We have characterized this low-granule basophil population in murine BM and spleen using in situ hybridization with the Hdc riboprobe and ultrastructural criteria (6). Their number and activity increase strikingly in peripheral organs during worm rejection (7), and they are revealed easily by their capacity to respond to hematopoietic growth factors (IL-3 or GM-CSF) or aggregated IgE by concomitant synthesis of histamine, IL-4, and IL-6 (8, 9). These medullary basophils can take up histamine from the environment through a process that does not involve H1, H2, or H3R, although H3R antagonists compete with histamine for uptake (10, 11). In the present study we addressed two major issues arising from these findings: the functions of histamine transported by medullary basophils, and the identity of the molecule that is responsible for this process. Here, we provide the first evidence that histamine can modulate the biologic activities of basophils through a transport system that is unrelated to its classical receptors, including the most recently discovered H4R. We identify the molecule that mediates this process as organic cation transporter (OCT) 3, and show that it is inhibited by available H3/H4R ligands. Furthermore, we demonstrate that this negative feedback is triggered by an increase of intracellular histamine, which exerts a transcriptional control of its own synthesis and that of associated pro-Th2 cytokines.

The role of the thymus in T cell commitment of hemopoietic precursor is yet controversial. We previously identified a major T cell progenitor activity in precursor cells isolated from bone marrow-derived spleen colonies. In this study, we characterize the properties of these pre-T cells. We demonstrate that they have unique phenotype and can be generated in a total absence of any thymic influence. Indeed, even when studied at the single-cell level, extrathymic T cell-committed precursors express T cell-specific genes. Moreover, these cells are not committed to a particular T cell differentiation pathway because they can generate both extrathymic CD8αα+ intraepithelial lymphocytes and thymus-derived conventional thymocytes. We also compared these pre-T cells with fully T cell-committed thymic progenitors. When tested in vitro or by direct intrathymic transfer, these cells have a low clonogenic activity. However, after i.v. transfer, thymus repopulation is efficient and these precursors generate very high numbers of peripheral T cells. These results suggest the existence of extra steps of pre-T cell maturation that improve thymus reconstitution capacity and that can be delivered even after full T cell commitment. Consequently, our studies identify a source of extrathymic progenitors that will be helpful in defining the role of the thymus in the earliest steps of T cell differentiation.

A number of recent studies have led to a reappraisal of the functional capacities of histamine in immunity and hematopoiesis. This change of perspective was provided by the following findings: (1) the evidence for multiple cellular sources of histamine, differing from mature basophils and mast cells by their ability to newly synthesize and liberate the mediator without prior storage, (2) the discovery of a novel histamine receptor (H 4 R), preferentially expressed on hematopoietic and immunocompetent cells, (3) the potential intracellular activity of histamine through cytochrome P450 and (4) the demonstration of a histamine–cytokine cross-talk. Indeed, cytokines not only modulate the degranulation process of histamine but also control its neosynthesis by the histamine-forming enzyme, histidine decarboxylase (HDC), at transcriptional and post-transcriptional levels. In turn, histamine intervenes in the intricate cytokine network, regulating cytokine production by immune cells through distinct receptors signaling distinct biological effects. This type of regulation is particularly relevant in the context of TH1/TH2 differentiation, autoimmunity and tumor immunotherapy.

Introduction Afin de remplir sa mission, l’EU-OSHA a besoin d’informations sur l’emergence des nouveaux risques qui menacent la securite et la sante au travail (SST). C’est pourquoi elle a lance une serie d’etudes sur ces themes depuis le debut des annees 2000. L’Observatoire europeen des risques a ete mis en place afin de disposer d’une vue d’ensemble paneuropeenne des tendances et defis communs, danticiper les changements et d’evaluer l’evolution technologique et sociale et l’impact potentiel sur le travail. Il fournit egalement des informations aux decideurs politiques, aux chercheurs et aux praticiens, aux gouvernements des Etats membres, et aux partenaires sociaux, afin de les aider a prevoir les risques emergents et a prendre des mesures. Une etude de definition et de priorisation de themes a pris en compte les changements imprevisibles dans la nature du travail, l’incertitude economique permanente liee a la crise financiere mondiale et les changements de nature societale, politique, economique et technologique pour identifier les themes d’etudes futures et animer le debat. L’EU-OSHA a aussi recemment realise une etude prospective des risques emergents dans les emplois verts, et publie une serie d’articles et d’expertises sur l’effet sur la SST de la robotique, de l’externalisation a grande echelle crowdsourcing), ou l’utilisation des drogues ameliorant la performance, vu dopants, en lieux de travail. Recemment, l’agence a entame un projet d’analyse de systemes d’alerte et de sentinelle des Etats membres. Un certain nombre de pays ont mis en place ces systemes afin de determiner des expositions et des maladies emergentes, d’identifier les groupes a risque, de mettre en place des regimes de prevention fondes sur des preuves et mieux cibler les efforts de prevention, et de contribuer a la reconnaissance de certaines maladies ne pouvant actuellement pas etre indemnisees. L’objectif de l’etude est d’etablir une typologie des systemes en place afin de mieux identifier les defis et avantages de l’utilisation d’un tel systeme. Ce projet devrait egalement contribuer a la mise en commun des informations sur les nouveaux problemes de sante lies a des expositions specifiques et d’identifier quelles sont actuellement les priorites des Etats membres pour l’identification des maladies emergentes secteurs, expositions, types de maladies). Enfin, il vise a contribuer a une meilleure comprehension de la relation de cause a effet et au developpement d’instruments de surveillance de sante cibles pour soutenir la reconnaissance precoce des risques au travail.

Arginase activity - mainly known for its involvement in urea formation in the liver - inhibits DNA synthesis in cultured mammalian cells(1). Arginase is synthesised and released by activated macrophages mediating immunosuppression during mixed leucocyte culture(2) and may be implicated in macrophage cytotoxicity during the anti-tumor(3), anti-parasite(4) and anti-viral(5) responses. Here Elke Schneider and Michel Dy discuss these aspects of arginase activity as well as more recent indications that arginase may be involved in the cell differentiation and/or proliferation taking place during the immune responses(6,7). A lymphokine with arginase-enhancing activity has been identified. By producing ornithine, arginase provides the unique precursor of polyamines which are essential for DNA synthesis(8).

Recently, a marked extramedullary myelopoiesis in Fas/CD95- or FasL/CD95L-deficient mice has been reported. In the present in vitro study, the mechanisms underlying Fas-induced apoptosis of normal peripheral colony-forming unit-C (CFU-C) progenitors in the spleen were analyzed. Surprisingly, it was found that clonogenic progenitors were protected from γIFN plus Fas-induced programmed cell death when Lin+ cells were removed from cultured splenocytes. The cells that rendered CFU-C sensitive to the activation of the Fas pathway did not belong to the T or the myelocytic–monocytic lineage but comprised a non–B-cell subset expressing the activation marker B220. Among CD19− B220+ splenocytes, nearly half were natural killer (NK) 1.1+ cells whose in vivo depletion or deficiency in RAG2-γc−/− mice abrogated the effect of Fas cross-linking. NK cells exerted their accessory function, at least in part, through tumor necrosis factor–α (TNF-α), which they readily produced during pretreatment with the anti-Fas/CD95 monoclonal antibody and IFN-γ and whose addition could compensate for the loss of sensitivity. In conclusion, this study provides evidence that peripheral clonogenic progenitors are not directly responsive to Fas cross-linking, even in the presence of IFN-γ, but require NK cells as a source of TNF-α to make them susceptible to this death pathway.

NKT cells are a remarkably versatile population whose functional capacities are determined by cytokines present in their microenvironment. In this study, we provide evidence for a new immunoregulatory effect of the proinflammatory cytokine IL-18 on NKT cells. We found that IL-18, mainly known for its involvement in NK cell activation and in Th 1 immune responses, substantially enhanced IL-4 production as well as the percentage of IL-4+ cells among NKT lymphocytes activated by their specific ligand α-galactosylceramide (α-GalCer). The effect of IL-18 on IL-4 production by activated NKT cells took place both in vivo and in vitro and was not affected by IL-12 which increased IFN-γ secretion in the same conditions. We show that NKT cells are the main targets for IL-18-induced IL-4 production since it occurred neither in NKT-deficient mice nor after stimulation of Th2 lymphocytes. Finally, we provide evidence that the IL-4 promptly generated by NKT cells in response to IL-18 plus α-galactosylceramide in vivo can effectively contribute to the adaptive Th2 immune response by up-regulating the early activation marker CD69 on B cells. Our data support the notion that, in contrast to the exclusive IFN-γ inducer IL-12, IL-18 acts in a more subtle manner as a costimulatory factor in both pro-Th1 and pro-Th2 responses depending on the nature of the stimulation and the target cells.

In this study, we examined the consequences of Fas deficiency on hematopoiesis in C57BL/6-lpr/lpr mice. We found a striking extramedullary increase in hematopoietic progenitor cells, comprising erythroid and nonerythroid lineages alike. These modifications preceded the lymphadenopathy, because early progenitors (colony-forming units-spleen [CFU-S] day 8) were already augmented in day-18 fetal livers of the lpr phenotype. Three weeks after birth, CFU-S increased in peripheral blood and spleen and colony-forming cells (CFU-C) began to accumulate 1 to 3 weeks later. Extramedullary myelopoiesis augmented progressively in Fas-deficient mice, reaching a maximum within 6 months. By then, mature and immature myeloid cells had infiltrated the spleen, the liver, and the peritoneal cavity. Similar changes occurred in C57BL/6-gld/gld mice, indicating that they resulted from Fas/FasL interactions. Medullary hematopoiesis was not significantly modified in adult mice of either strain. Yet, the incidence of CFU-S decreased after Fas cross-linking on normal bone marrow cells in the presence of interferon γ, consistent with a regulatory function of Fas/FasL interactions in early progenitor cell development. These data provide evidence that Fas deficiency can affect hematopoiesis both during adult and fetal life and that these modifications occur independently from other pathologies associated with the lpr phenotype.

In the present study, we show that UT7D1 cells, derived from the pluripotent cell line UT7, express high levels of histidine decarboxylase (HDC) mRNA spontaneously. These cells conserve the ability to differentiate into megakaryocytes upon stimulation with PMA, while greatly increasing their HDC activity. We provide evidence that enhanced HDC activity reflects the basophil rather than the megakaryocytic differentiation potential of UT7DI cells. Indeed, in addition to HDC mRNA, they express spontaneously several other mRNA coding for molecules present in basophils (FcepsilonRI, CCR3, IL-4Ralpha, IL-5Ralpha). Furthermore, the basophil antigen Bsp-1 is displayed on the surface of some UT7D1 cells in response to PMA concomitantly with increased histamine synthesis and mRNA expression of typical basophil-derived cytokines (IL-6, IL-4, and IL-13). Nevertheless, PMA cannot sustain the differentiation of this lineage, because mRNAs for basophil markers gradually diminish during long-term culture, whereas molecules associated with the megakaryocytic lineage remain prominent. In support of the notion that HDC activity is not related with megakaryopoiesis, we show that PMA-induced CD41 expression and PDGF transcription occurs in the K562 cells, though neither HDC mRNA nor any known basophil marker are expressed in these conditions. In contrast, all these markers are expressed in the basophilic leukemia cell line KU812F. Interestingly, the megakaryocytic cell line HEL produces also substantial amounts of histamine and expresses FcepsilonRI, thus revealing its basophil differentiation potential. HEL as well as KU812F need not be stimulated with PMA to react with Bsp-1 mAb, suggesting that they are more engaged into the basophil differentiation scheme than UT7D1. Other leukemic cell lines unrelated to the megakaryocyte or basophil lineage, like HL60 and U937 do neither synthesize histamine nor express basophil markers before or after PMA stimulation. To our knowledge, this is the first evidence for a factor-dependent cell line with megakaryocyte/basophil bipotentiality with which early stages of basophil commitment can be analyzed.

Murine low-density bone marrow cells sorted from the blast cell window on the basis of high rhodamine-123 retention (Rh-bright), are highly enriched in histamine-, IL-4-, and IL-6-producing cells. We established by in situ hybridization that up to 50% of this population (around 0.25% of the whole bone marrow) coexpressed the transcripts for these molecules upon stimulation with 1L-3. Rh-bright cells were also positive for mRNA encoding the alpha, beta, and gamma chains of the Fc(epsilon)RI which was functional since aggregated IgE induced the same percentage of cells hybridizing with the HDC probe as IL-3. Clonogenic progenitors and histamine- and cytokine-producing cells copurified in the Rh-bright population, but could be distinguished by their c-kit expression, CFU-C being more frequent in the c-kit(high) fraction, while histamine and IL-6 producers were enriched in the kit(low) counterpart. Ultrastructural analysis of Rh-bright cells revealed essentially two subsets, namely undifferentiated blast cells and basophil precursors. No other lineage-committed population was enriched by this sorting procedure, and it can therefore be concluded that coexpression of HDC, IL-6, and IL-4 transcripts in response to IL-3 or aggregated IgE takes place mainly in hematopoietic precursors belonging to the basophil lineage.

We will respond to Kahn-Horwitz, Roffman and Teitelbaum (1998) by raising two concerns. In their article the authors use the term ‘LD’ loosely to refer to ‘learning differences’, and we would be interested to have more details of the criteria by which these individuals were identified. (Most educators use ‘LD’ to refer to ‘specific learning difficulties’.) Secondly, we would like to encourage the authors to provide a more precise explanation of the instructional methods they recommend for remediation in the foreign language. © 1998 John Wiley & Sons, Ltd.

INTRODUCTION AND OBJECTIVES: The poor prognosis of renal cell carcinoma (RCC) is caused by a high risk of metastasis. 30% of RCC patients develop bone metastases during the course of disease. A method of predicting bone metastasis would benefit the otherwise poor outcome of this patient group. The aim of this study was to elucidate the mechanisms that lead to organ-specific metastasis of RCC in bones and thereby predict bone metastasis. METHODS: In 30 RCC tissue specimens and 9 RCC primary cell lines collected from patients who had developed no metastases, lung or bone metastases within 5 years after nephrectomy (each 10 RCC tissue specimens, each 3 RCC cell lines) expression and/or activity of 46 cellular signaling molecules were quantified by phosphokinase array and Western blot analyses. To investigate metastatic behavior, migration of the primary RCC cells was analysed in a Boyden chamber with 10 g/ml fibronectin as chemotaxin, and adhesion to extracellular matrix compounds fibronectin, collagen I and IV was determined after cell staining with crystal violet. RESULTS: In RCC tissue specimens and primary cells from patients who developed bone metastases, a higher expression of 5 integrins, higher activity of Akt and FAK and a lower expression of PTEN were detected, compared to those from patients without or with lung metastases. These results show an enhanced chemotactic migration (13-fold) of bone metastatic RCC cells and adhesion to fibronectin (6-fold) or collagen type I (8-fold) both components of the bone matrix. CONCLUSIONS: Specific characteristics such as expression and activity of cell signaling mediators and cellular behavior of the primary tumor determine the location of subsequent metastasis in RCC and could be used as a prognostic marker for bone metastasis. This should be considered during follow-up care.

Background It is commonly acknowledged that asthma is exacerbated by viral infections. On the other hand, basophil infiltration of lung tissues has been evidenced postmortem in cases of fatal disease, raising the question of a possible link between these two observations. Objectives Herein, we addressed the relationship between asthma exacerbation by viral infection and basophil activation and expansion by investigating how stimulation with the dsRNA polyadenylic/polyuridylic acid [poly(A:U)] affected basophil activities and recruitment in an allergic airway inflammation model. Methods The effect of dsRNA on basophils was assessed by measuring the cytokine levels produced upon stimulation. We used an OVA-induced experimental model of allergic asthma. Airway hyperreactivity, recruitment of infiltrating cells, and cytokine production were determined in the lung of mice having received poly(A:U), as compared with untreated controls. The exacerbating effect of basophils was assessed both by adoptive transfer of poly(A:U)-treated basophils and by their in vivo depletion with Ba103 antibody. Results We found that in vitro treatment with poly(A:U) increased basophil functions by inducing TH2-type cytokine and histamine production, whereas in vivo treatment increased peripheral basophil recruitment. Furthermore, we provide the first demonstration for increased infiltration of basophils in the lung of mice suffering from airway inflammation. In this model, disease symptoms were clearly exacerbated upon adoptive transfer of basophils exposed to poly(A:U), relative to their unstimulated counterpart. Conversely, in vivo basophil depletion alleviated disease syndromes, thus validating the transfer data. Conclusions Our findings provide the first evidence for airway inflammation exacerbation by basophils following dsRNA stimulation.

Basophils co-express FcεRIα and CD49b, the α-2 chain of integrin-type receptor VLA-2 (α2β1), which recognizes type-1 collagen as a major natural ligand. The physiological relevance of this integrin for interactions with extracellular bone marrow matrix remains unknown. Herein, we examined the expression of several receptors of this family by bone marrow-derived basophils sorted either ex-vivo or after culture with IL-3. Having established that both populations display CD49d, CD49e and CD49f (α-4, α-5 and α-6 integrins subunits, respectively), we addressed receptor functions by measuring migration, adhesion, proliferation and survival after interacting with matched natural ligands. Type I collagen, laminin and fibronectin promoted basophil migration/adhesion, the former being the most effective. None of these ligands affected basophil viability and expansion. Interactions between basophils and extracellular matrix are likely to play a role in situ, as supported by confocal 3D cell imaging of femoral bone marrow sections, which revealed basophils exclusively in type-1 collagen-enriched niches that contained likewise laminin and fibronectin. This is the first evidence for a structure/function relationship between basophils and extracellular matrix proteins inside the mouse bone marrow.

Based on cross-linguistic and interdisciplinary research of several decades that bridges learning an additional language with the field of learning differences/disabilities, this article shares research-evidenced practices to effectively address the needs of struggling foreign and second language learners of English in Brazil. These multisensory structured strategies enhance pronunciation, listening, reading and writing skills and strengthen grammar and vocabulary competencies of struggling learners. The selected multisensory structured metacognitive strategies can easily be infused into existing English as a foreign/second language curricula.

INTRODUCTION AND OBJECTIVES: Structural changes in tubule cells during clamp ischemia are well characterized for animal models, but their timing and extent in the human kidney has not been established and may differ significantly. To better define the human response, we biopsied uninvolved areas of kidney in patients undergoing open partial nephrectomy for renal masses. METHODS: Biopsies of 40 patients undergoing PN were obtained at specified time intervals: before renal artery clamping, then during periods ranging from 15 to 60 min. of warm and cold ischemia (80% 30 min.), and then after 5 minutes of reflow. These biopsies were assessed for ultrastructure (N 39) and for immunofluorescence and rhodamine phalloidin staining (N 22). RESULTS: During the clamp period, apical membrane structure was remarkably well preserved with only patchy brush border clubbing, fragmentation, desquamation and blebbing and not in all patients. Mitochondria developed progressive swelling, which paradoxically was more prominent in distal than proximal tubule cells. This resolved during the 5 minutes of reflow in most cells in most patients, but persistence of swelling and development of matrix condensation occurred occasionally. Using a composite 0-5 scale covering the full spectrum of ultrastructural changes, average scores were: Preclamp 1.02 0.07, End clamp 2.18 0.07, Post clamp 1.86 0.09. Consistent with the ultrastructure, staining for F-actin with rhodamine phalloidin was well preserved. Immunsotaining for phosphotyrosine, which reflects cellular ATP content was decreased in 68.4% of the clamp biopsises and 52.6% of the postclamp biopsies with larger changes in proximal tubules, however B1 integrin was decreased in only one post clamp biopsy. ICAM-1 expression in peritubular capillaries was increased in 46.7% of the clamp biopsies and 66.7% of post clamp biopsies. None of the patients developed acute kidney injury. CONCLUSIONS: These data provide the first detailed analysis of the structural response of the human kidney to clamp ischemia and document many of the expected structural alterations based on prior animal work, but indicate a greater than expected resistance to injury in this commonly used clinical application of clamp ischemia.

INTRODUCTION AND OBJECTIVES: Although a number of molecules have been implicated in the process of formation of cancer metastases, the organ-selective nature of cancer cells is still poorly understood. Renal cell carcinoma (RCC) often metastasize into bones, a calcium enriched tissue. We analyzed the influence of the calcium sensing receptor (CaSR) in RCC and an enhanced extracellular calcium concentration in processes of metastatic spread. METHODS: In 33 matched RCC specimens, 11 non-metastasized, 11 metastasized into the lung and 11 metastasized into bones five years after nephrectomy, CaSR was quantified by RT-PCR and Western blot analyses. To investigate the influence of enhanced extracellular calcium on the formation of metastases, primary RCC cells were isolated from patients developing bone, lung and no metastasis five years after nephrectomy (each 3 cell lines). Cell proliferation after calcium treatment (2.5, 5 and 10 M) was quantified by BrdU incorporation. Cell migration was determined in a Boyden chemotaxis assay with calcium as chemotactical agent (10 M). Expression and activity of intracellular signal transduction mediators were analyzed by a human phospho kinase array and Western blot analyses. RESULTS: Compared to non-metastasizing RCC, CaSR mRNA expression was 10.8-fold increased and CaSR protein level was 1.5-fold increased in tumor specimens of patients developing bone metastases. In primary RCC cells with a high bone metastastic potential CaSR expression was 3.7-fold higher compared to non-metastasizing RCC cells. Calcium treatment of bone-metastasizing RCC cells, but not of non-metastasizing cells, induced a concentration dependent enhancement of proliferation. In a Boyden chamber experiment with calcium as chemo attractant, RCC cells from patients with bone metastases showed a 9.4-fold higher migratory potential compared to cells from patients without metastases. In lung metastatic RCC cells migration was only 1.7-fold enhanced. The enhanced proliferation and migration of cells with high potential to build bone metastases seem to be caused by an activation of Akt and a highly increased integrin alpha 5 expression. Additionally, the tumor suppressor PTEN was markedly reduced in tumors metastasizing into bones and after calcium treatment, promoting tumor progression. CONCLUSIONS: Our results indicate that formation of bone metastases of RCC is caused by an enhanced expression of the CaSR. Extracellular calcium has a promoting effect on cell migration and proliferation of bone metastasizing RCC cells via Akt signalling and integrin alpha 5.

Similar to interleukin-3 (IL-3), IgE acts on murine bone marrow cells by inducing histamine production. This effect does not result from degranulation of histamine-containing cells, but from histamine synthesis, as assessed by the following findings. (1) The histamine content of freshly isolated bone marrow cells is too low to account for the increase in extracellular histamine levels. (2) Neither IL-3 nor IgE induced histamine production in the presence of the specific inhibitor of histidine decarboxylase (HDC), the histamine-forming enzyme. (3) Both the enzymatic activity and the mRNA expression of HDC were enhanced in response to IL-3 or IgE. Artificial aggregation or formation of IgE immune complexes augmented ther effect on histamine synthesis, indicating that the aggregated form is responsible for this biologic activity. Yet, it is apparently not mediated by Fc epsilon RI because their cross-linkage by dinitrophenyl bovine serum albumin after presensitization with IgE did not induce histamine production by hematopoietic progenitors. Among other aggregated isotypes tested, only IgG2a and, to a lesser extent, IgG1 had a consistent but lower effect, whereas IgM and IgA were completely inactive. The target cells of IL-3 and IgE in terms of histamine synthesis do not belong to mature bone marrow populations, especially mast cells. They copurify with hematopoietic progenitors in the low-density layers of a discontinuous Ficoll gradient where they represent around 5% of the cells, as determined by in situ hybridization. This percentage remained the same, regardless of whether the cells were stimulated by IgE or IL-3 alone or by a combination of both, suggesting a common responder cell. In accordance with this notion, histamine-producing cells could not be distinguished from each other on the basis of density, size and internal structure, or rhodamine (Rh) retention. Finally, the effect of IgE is not caused by the induction of IL-3 because anti-IL-3 antibodies did not abrogate the effect of IgE.